The Novel Role of PGC1α in Bone Metabolism.

Cinzia Buccoliero,Silvia Colucci,Maria Grano,Graziana Colaianni,Francesco Gaccione,Manuela Dicarlo,Patrizia Pignataro

doi:10.3390/ijms22094670

Abstract

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes.

Highlights

The peroxisome proliferator-activated receptor γ (PPARγ) and coactivator-1s (PGC-1s) are members of a family of transcriptional coactivators consisting of PGC1α, Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1β), and PGC-1 related coactivator (PRC), all of which play key roles in the regulation of mitochondrial biogenesis in all tissues [1]
Genome-wide association studies (GWAS) in humans and studies in mice carrying mitochondrial DNA mutations have suggested that defective mitochondria or damaged mtDNA are associated with osteoporosis [3,4]
Overexpression of superoxide dismutase 2 (SOD2) markedly reverted reduction of oxygen consumption, alkaline phosphatase (ALP) staining and Runx2, Col1α1, and Ocn mRNA level [10]. These findings indicated a key role of SOD2 in Sirtuin 3 (SIRT3) knockdown-induced inhibition of osteogenic differentiation and mitochondrial activity [10]

Summary

Introduction

The peroxisome proliferator-activated receptor γ (PPARγ) and coactivator-1s (PGC-1s) are members of a family of transcriptional coactivators consisting of PGC1α, Peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1β), and PGC-1 related coactivator (PRC), all of which play key roles in the regulation of mitochondrial biogenesis in all tissues [1]. Genome-wide association studies (GWAS) in humans and studies in mice carrying mitochondrial DNA (mtDNA) mutations have suggested that defective mitochondria or damaged mtDNA are associated with osteoporosis [3,4] Along these lines, mitochondrial dysfunction increasingly appears to be one of the most important cellular features driving the aging process [5]. The first study, demonstrating that PGC1α, stimulated by parathyroid hormone (PTH), synergizes with nuclear related receptor-1 (Nurr1) to transactivate target genes in osteoblastic cells, dates back to 2006 [8]. Several studies both in vitro and in vivo on mouse models with PGC1α deletion in the whole-body or with conditional deletion in skeletal stem cells or osteoblasts have since been performed (Table 1). We aim to summarize the current knowledge of the role of PGC1α as an anabolic factor in bone metabolism in both physiological condition and bone related pathologies, with the focus on paving the way for further studies in the future

The Bone Phenotype of PGC1α Knock-Out Mice

PGC1α Role in Bone-Related Pathologies

Findings

Conclusions